Producing diuretic and saluretic effects with benzofuran carboxylic acid derivatives

ABSTRACT

5-(2-Bromo-2-bromomethyl-alkanoyl)-benzofuran-2-carboxylic acids and their pharmaceutically acceptable salts with bases have diuretic and saluretic activities. A typical embodiment is 5-(2bromo-2-bromomethyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid. A method of producing a diuretic and simultaneously a saluretic effect comprising administering said compounds to warmblooded animals as well as pharmaceutical composition containing said compounds are provided.

United States Patent Zergenyi et al. [451 July 11, 1972 [54] PRODUCING DIURETIC AND SALURETIC EFFECTS WITH R f rences Ci ed BENZOFURAN CARBOXYLIC ACID U ED T E TE DERIVATIVES 5 AT SPA NTS 3,235,566 2/ I966 Schoetensack et al. ..424/285 Inventors: Janos Zergenyi, Richen; Ernst Habicht,

Oberwil, both of Switzerland Assignee: Geigy Chemical Corporation, Ardsley,

Filed: May 6, 1970 Division of Ser. No. 746,267, July 22, 1968, Pat. No. 3,557,152.

US. Cl. ..424/285 Int. Cl. ..A6lk 27/00 Field of Search ..424/285 Primary ExaminerSam Rosen Anorneyl(arl F. Jorda and Bruce M. Collins ABSTRACT 5-(2-Bromo-2-bromomethyl-alkanoyl)-benzofuran-2-carboxylic acids and their pharmaceutically acceptable salts with bases have diuretic and saluretic activities. A typical embodiment is 5-(2-bromo-2-bromomethyl-butyryl)-6-methylbenzofuran-Z-carboxylic acid. A method of producing a diuretic and simultaneously a saluretic effect comprising administering said compounds to warm-blooded animals as well as pharmaceutical composition containing said compounds are provided.

4 Claims, No Drawings PRODUCING DIURETIC AND SALURETIC EFFECTS WITH BENZOFURAN CARBOXYLIC ACID DERIVATIVES CROSS REFERENCE TO RELATED APPLICATION This application is a division of our application Ser. No. 746,267 filed July 22, 1968 now US. Pat. No. 3,557,152.

DETAILED DESCRIPTION The present invention concerns heterocyclic carboxylic acids, a method of producing diuresis and saluresis, as well as pharmaceutical compositions.

More particularly the present invention pertains to heterocyclic carboxylic acids of the formula I R is hydrogen or lower alkyl, Y is hydrogen or methyl, and each of Z, and Z, taken individually is hydrogen, lower alkyl, lower alkoxy, fluoro, chloro or bromo; and the pharmaceutically acceptable salts of said compounds with bases.

It has been found that the new compounds have valuable vpharmacological properties. In particular, they have diuretic and saluretic activity. These properties characterize these 1 compounds as suitable for the treatment of disturbances which are due to insufficient excretion of urine and of electrolytes, particularly of sodium chloride. Such disturbances are the cause of oedema and hypertension. These new substances increase considerably the excretion of urine and of sodium and chlorine'ions in dogs and in rabbits.

In the heterocyclic carboxylic acids of Formula I, Z, takes the 4- or 6- position and Z, the 6- or 7- position. By the term lower alkyl and the derivation thereof using the root alk,

namely alkoxy, is intended a group comprising a straight orbranched hydrocarbon chain of from one to four carbon atoms. Representative of lower alkyl groups are thus, e.g. the

methyl, ethyl, propyl, isopropyl, butyl or the tert. butyl group. Embraced by the term lower alkoxy are such groups as the methoxy, ethoxy, propoxy, isopropoxy, butoxy or the sec. butoxy group.

Compounds of the formula I are produced according to a first process by adding halogen to a compound of formula II wherein R, Y, Z, and Z, have the meanings given in formula I.

This addition of halogen is carried out e.g. by adding the I equimolar amount of chlorine or bromine to the stirred solution of the compound of formula II in an appropriate solvent, such as e.g. glacial acetic acid, nitrobenzene or a halogenated hydrocarbon.

The starting material of formula II can be produced in a first processby reacting, according to Friedel-Crafts, a compound of formula III Y [C0011 O 20. ture, e.g. benzofuran-2-carboxylic acid [cf. R. Fittig et al.,

- wherein R has the meaning given in formula I, with aluminum wherein Y, Z, and 2, have the meanings or with a carboxylic acid anhydride of formula V wherein R has the meaning given in formula I, and Q represents a halogen atom.

Starting materials of formula III are described in the litera- Ann. Chem. 216, 162 (1883)], 6-methyl-benzofuran-2-carboxylic acid [cf. K. von Auwers, Ann. Chem. 408, 255 (l915)]an'd 4,6-dimethyl-benzofuran-2-carboxylic acid (cf. F. M. Dean et al. J. Chem. Soc. 1953, 1250). These compounds can be acylated in the 4-position, e.g. according to Friedel-Crafts in the presence of aluminum chloride in nitrobenzene.

As halogen, Q ispreferably chlorine or bromine. Suitable catalysts for the reaction according to FriedeLCrafts are, e.g. in particular aluminum chloride and stannic chloride, also zinc chloride, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid or pyrophosphoric acid. The acids mentioned are used, preferably, when a carboxylic acid anhydride is the acylating agent. The reaction is preferably performed in a solvent. As such can be used, e.g. aliphatic or cycloaliphatic hydrocarbons such as heptane or cyclohexane, nitrated hydrocarbons such as nitromethan'e, nitrocyclohexane or nitrobenzene, or halogenated hydrocarbons such as carbon tetrachloride, ethylene chloride, methylene chloride, 0-

: dichlorobenzene and carbon disul fide.

Advantag'eouslythe starting materials'of formula II can also be produced by a second process. Reacting according to Friedel-Crafis a compound of formula III with a carboxylic acid chloride of formula VI chloride in nitrobenzene, yields a compound of formula VI] COOH GHQ-Am z,

GOOH 0 Z, (VIII) wherein R, Y, Z, and '2 have the meanings given under formula Iand Am represents a tertiary amino group, respectively the acid addition salts thereof. Suitable secondary amines are e.g. dimethylamine, diethylamine, pyrrolidine, piperidine, morpholine or hexahydro-lH-azepine.

The Mannich derivatives of formula VIII, respectively their acid addition salts, are isolated or used as raw products in the next step. They are in a simple manner transformed to the corresponding methylene compounds of formula II by heating them in the presence of a weak base in a solvent containing hydroxyl groups.

Examples of weak bases are sodium acetate or sodium hydrogen carbonate; they are preferably used in water or lower fatty acids, e.g. in glacial acetic acid.

Compounds of formula I can be obtained according to a second process by reacting a compound of formula III according to Friedel-Crafts with carboxylic acid chlorides of formula IX R- I COCI wherein R and Q have the meanings given in formula I. For the formation of pharmaceutically acceptable salts can be used inorganic or organic bases, such as alkali or alkaline earth hydroxides, carbonates or bicarbonates, e.g. the sodium,

potassium, magnesium or calcium derivatives,

triethanolarnine or choline. Such salts of bases are produced by mixing the compound of formula I with the equivalent amount of the desired base in a suitable solvent such as water,

mixtures of water with an organic solvent or in organic solvents alone such as methanol, ethanol or propanol and isolating the salts formed in a conventional manner.

The compounds of the invention have been found to have valuable pharmacological properties, especially diuretic and saluretic activities combined with a very low order of toxicity. These favorable properties render the compounds of formula I and their pharmaceutically acceptable salts with bases suitable for the treatment of disturbances which are due to insufficient excretion of urine and of electrolytes, particularly of sodium chloride. Such disturbances are the cause of oedema and hypertension.

The diuretic and saluretic effects of the compound of the invention are illustratively demonstrated in dogs and rabbits. Thus it can be shown by conventional pharmacological experiments that 5-(2-bromo-2-bromomethyl-butyryl)-6-methylbenzofuran-Z-carboxylic acid administered orally or parenterally in amounts of 5 mg/kg to dogs and rabbits increase the excretion of urine and simultaneously of sodium and chlorine ions to a considerable extent. At the same no noticeable side effects are observed.

The new active substances or the pharmaceutically acceptable salts thereof are preferably administered orally.

The daily dosages vary between 50 and 1,000 mg for warmblooded animals. Suitable dosage units such as dragees and tablets, preferably contain 25-500 mg of an active substance according to the invention, i.e. -80 percent of a compound of formula I. They are produced by combining the active substance with, e.g. solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, to form tablets or dragee cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestufi's can be added to these coatings, e.g. to distinguish between varying dosages of active substance.

Other suitable dosage units are hard gelatine capsules as well as soft closed capsules made from gelatine and a softener, such as glycerine. The hard gelatine capsules preferably contain the active substance as a granulate, e. g. in admixture with fillers such as maize starch, and/or lubricants such as talcum or magnesium stearate and, optionally, stabilizers such as sodium metabisulfite (Na S- O or ascorbic acid. In soft gelatine capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols to which stabilizers can also be added.

The following examples further illustrate the production of the new compounds of formula I of hitherto undescribed intermediate products, as well as the production of pharmacological compositions, but these are by no means the sole methods of producing same. The temperatures are given in degrees Centigrade.

EXAMPLE 1 a. A solution of 0.65 g of bromine in 1 ml of chloroform is added dropwise at room temperature to a stirred solution of 1.0 g of 5-( Z-methylene-butyryl)-6-methyl-benzofuran-2-carboxylic acid. This addition takes 5 minutes and the reaction mixture is left to stand for 20 minutes. The chloroform is then evaporated under reduced pressure and the residue is recrystallized from ethyl acetate. Thus 5-( 2-bromo-2- bromomethylbutyryl)-6-methyl-benzofuran-2-carboxylic acid is obtained, which melts with decomposition at 193l95.

Analogously to this example the following compounds are produced:

b. 5-(2-bromo-2-bromomethyl-butyryl)-6-ethoxy-benzofuran-Z-carboxylic acid, M.P. 174176 dec. (benzene-heptane), benzofuran-2-carboxylic acid;

0. 5-( 2-bromo-2-bromomethyl-propionyl)-6-methylbenzofuran-Z-carboirylic acid, M.P. 2l0-211 dec. (ethyl acetate), starting from 5-(2-methylene-propionyl)-6-methylbenzofuran-Z-carboxylic acid;

d. 5-(2-bromo-2-bromomethyl-butyryl)-3,6-dimethylbenzofuranZ-carboxylic acid, M.P. 193-l94 dec. (benzene), starting from 5-(2-methylenebutyryl)-3,6-dimethyl-benzofuran-2-carboxylic acid;

e. 4-chloro-5-(2-bromo-2-bromomethyl-butyryl)-benzofuran-Z-carboxylic acid, M.P. 193-194 dec. (benzene), starting from 4-chloro-5-( Z-methylene-butyryl)-benzofuran 2-carboxylic acid;

f. 5-(2-bromo-2-bromomethyl-valeroyl)-6methyl-benzofuran-Z-carboxylic acid, M.P. 205-206 dec. (ethyl acetate), starting from 5-(Z-methyIene-valeroyl)-6-methyl-benzofuran- 2-carboxylic acid;

EXAMPLE 2 A stream of gaseous chlorine is blown at room temperature into a stirred solution of 1.1 g of 5-(2-methylene-butyryl)-6- ethyl-benzofuran-Z-carboxylic acid in 20 ml of chloroform. The introduction of chlorine is interrupted when a persisting yellow coloring in and above the solution is attained. The reaction mixture is then stirred for 15 minutes. After this, the chloroform is removed in vacuo and the residue is recrystallized from benzene-hexane. Thus 5-( 2-chloro-2-chloromethylbutyryl)-6-ethyl-benzofi.iran-2-carboxylic acid is obtained, M.P. l58-159.

The following examples described the production of starting materials and intermediates:

EXAMPLE 3 5-Alkanoyl-benzofuran-2-carboxylic acids a. To a stirred suspension of 10 g of 6-methyl-benzofuran-2- carboxylic acid in 30 ml of nitrobenzene is added at 0 in portions 28 g of pulverized aluminum chloride whereby care is taken that the temperature remains below 10". Butyryl chloride (9 g) is dropped into the mixtureat 10 whereupon stirring is continued for 24 hours at room temperature. The mixture is then poured on 300 g of ice and 50 ml of concentrated hydrochloric acid and the resulting suspension is extracted with ether. The organic phase is washed with water and reextracted with aqueous sodium hydrogen carbonate solution. The sodium hydrogen carbonate solution is adjusted starting from 5-(Z-methyIene-butyryl)-6ethoxyto pH 3 with concentrated hydrochloric acid and stirred for 1 hour whereupon a precipitate is formed which is filtered, washed with water and dissolved in ethyl acetate. This organic solution is dried and evaporated in vacuo. The residue is recrystallized from ethylacetate/dioxan to give 5 butyryl-6- methyl-benzofuran-Z-carboxylic acid, M.P. 155 -l57.

In analogous manner as described above are prepared the following alkanoyl-benzofuran-2-carboxylic acids:

b. 5-butyryl-fi-ethoxy-benzofuran-2carboxylic acid, M .P.

203-205 (ethanol), from 6-ethoxy-benzofuran-2-carboxylic ml of 4N sodium hydroxide solution are added. A clearso ly tion is formed. 20 g of sodium borohydride are added and the whole is stirred for 5 hours at room temperature. The solution is then cooled with ice and hydrochloric acid is added dropwise until a pH of 3-4 has been attained. The suspension is stirred for another half hour, whereupon the 3-chloro-4-(lhydroxy-butyl)-phenol is filtered off undersuction. it is used immediately in the crude state.

h. The moist crystal mass of 3-chloro-4-(1-hydroxy-butyl)- phenol is added to a solution of 200 g of sodium hydroxide in 500 ml of water, the solution formed is heated to 70 and 150 g of chloroformare added dropwise within 2 hours. During the addition, the temperature of the reaction mixture must be 7080. The mixture is stirred for 20 minutes at 70 and then cooled to room temperature. The sodium salt of 3-chloro-4- (1-hydroxy-butyl)-2-formyl-phenol precipitates and is filtered f under tion- Thiscrude sodium salt is slurried in water, the pH'is a'djusted to 3 with hydrochloric acid and the slurry is extracted twice with ether. The ether extracts are washed with water, dried over magnesium sulfate and concentrated. The residue, crude 3-chloro-4-( l-hydroxy-butyl)-2-formyl phenol (30 g) is used in the crude state.

i. 30.0 g of crude 3-chloro-4-( l-hydroxy-butyl)-2-formyl phenol are dissolved in 100 ml of methylethyl ketone. 20 g of potassium carbonate are added and the mixture is refluxed while stirring. 30 g of bromomalonic acid diethyl ether are then added dropwise within 10 minutes whereupon the reaction mixture is refluxed for 5 hours while stirring. The solvent is then distilled off, the residue is taken up in water, concentrated hydrochloric acid is added until pH 3 is attained and the mixture is extracted twice with ether. The combined ether solutions are washed with water, dried over magnesium sulfate and concentrated. A solution of 20 g of potassium hydroxide, 20 ml ofwater and 200 ml of ethanol is added to the residue and the mixture is refluxed for 2 hours. 800 ml of water are then added and the aqueous-alkaline solution is washed twice with ether. The aqueous solution is acidified with concentrated hydrochloric acid and extracted twice with ether. The ether extracts are dried and concentrated. The residue is recrystallized from benzene ethylacetate to give 8 g of 4- chloro-5-( l-hydroxy-butyl )-benzofuran-2-carboxylic acid, M.l. l73l75.

j. 7.6 g of 4-chloro-5-(l-hydroxy-butyl)-benzofuran-2-carboxylic acid are dissolved in 80 ml of acetone, the solution is cooled to 0 and a solution of 2.2 g of CrO in 0.5 ml of concentrated sulfuric acid and 6 ml of water is added. The reaction mixture is stirred for minutes, diluted with water and extracted with ether. The combined ether layers are dried over magnesium sulfate and concentrated. The residue is recrystallized from benzene/ethyl acetate and yields S-butyryl- 4-chloro-benzofuran-2-carboxylic acid, M.P. 133l34.

EXAMPLE 4 5-(2-Methylene-alkanoyl)-benzofuran-2-carboxylic acids a. A mixture of 4 g of 5-butyryl-6-methyl-benzofuran-2-carboxylic acid, 0.82 g of paraformaldehyde, 1.64 g of dimethylamine hydrochloride and ml of dioxan is stirred and refluxed for 5 hours, and then evaporated in vacuo. The residue is refluxed for 2 hours together with 30 ml of glacial acetic acid and 3 g of dry sodium acetate. The solvent is evaporated in vacuo and the residue is triturated with 50 ml of water and acidified with cone. hydrogen chloride to pH 3. T hesuspension is stirred for about 30 minutes. The precipitate is removed by filtration, washed with water, dried'in vacuo at 60 and recrystallized from benzene/hexane to give 5-(2- methylene-butyryl)-6-methyl-benzofuran-2carboxylic acid, M.P. 14l-l42.

In analogous manner as described above are prepared the following intermediates: I

b. S-(Z-Methylene-butyryl)-6-ethoxy-benzofuran-Z-carboxylic acid, M.P. l39-l4l (ethanol/water), from 5-butyryl-6- ethoxy-benzofuran-Z-carboxylic acid;

c. 5-(2-methylene-propionyl)-6-methyl-benzofuran-2-carboxylic acid, M.P. l85l86 (ethyl acetate), from S-propionyl-6-methyl-benzofuran-2-carboxylic acid;

d. 5-(2-methylene-butyryl)-3,6-dimethyl-benzofuran-Z-carboxylic acid, M.P. l52-l54 (benzene/heptane), from S-butyryl-3 ,6-dimethyl-benzofuran-2-carboxylic acid;

e. 5-(Z-methylene-butyryl)-4-chloro-benzofuran-Z-carboxylic acid, M.P. 160-162 (benzene/ethyl acetate), from 5- I valeroyl-6-methyl-benzofuran-Z-carboxylic acid.

g. 5-(2 -methylene-butyryl)-6-ethyl-benzofuran-2-carboxylic acid, MP. l2l-l22 (benzene), from 5-butyryl-6-ethylbenzofuran-Z-carboxylic acid.

EXAMPLE 5 while stirring. Stirring is continued for 20 minutes when i this temperature is reached. The reaction mixture is then poured on to 2 kg of crushed ice and extracted with 500 ml of ether. The ether extract is washed with 200 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue consists of crude 7-ethylcoumarine, which is used without purification.

b. 30.4 g of this 7-ethyl-coumarine are dissolved in 40 ml of chloroform and a solution of 29 g of bromine in 20 ml of chloroform are added dropwise thereto. The reaction mixture is stirred and the temperature is kept at 2025 by immersing the reaction vessel from time to time into an ice bath. Stirring is continued at room temperature after all the bromine is added, The chloroform is then removed under reduced pressure at 50 and the residue is added in portions to a solution of 80 g potassium hydroxide in ml of ethanol which was prec. The other 2,, Z -substituted benzofuran-Z-carboxylic acids used as starting materials in Example 3 are known and are prepared in accordance with the publications mentioned above.

The following examples further illustrate the production of tablets and dragees:

EXAMPLE 6 l,000 g of -(2-bromo-2-bromomethyl-butyryl)-6-methylbenzofuran-Z-carboxylic acid are mixed with 500 g of lactose and 270 g of potato starch, the mixture is moistened with an aqueous solution of 8 g of gelatine and granulated through a sieve. After drying, 60 g of potato starch, 60 g of talcum, 10 g of magnesium stearate and g of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets each weighing 20 mg and containing 100 mg of active substance. If desired, the tablets can be grooved for better adaptation of the dosage.

EXAMPLE '7 A granulate is produced from 1,000 g of 5-(2-bromo-2- bromomethyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid, 345 g of lactose and the aqueous solution of 6 g of gelatine. After drying, the granulate is mixed with 10 g of colloidal silicon dioxide, 40 g of talcum, 40 g of potato starch and 5 g of magnesium stearate and the mixture is pressed into l0,000 dragee cores. These are then coated with a concen-.

wherein Q is chloro or bromo;

R is hydrogen or lower alkyl;

Y is hydrogen or methyl; and each of Z and Z taken individually is hydrogen, lower alkyl, lower alkoxy, fluoro, chloro or bromo; or of a pharmaceutically acceptable salt of said compound with a base.

2. The method according to claim 1 wherein said compound is 5-(2-bromo-2-bromomethyl-butyryl)-6-methyl-benzofuran- Z-carboxylic acid or a pharmaceutically acceptable salt of said compound with a base.

3. A pharmaceutical composition comprising a combination in dosage unit form of a pharmaceutical carrier and an amount sufficient to produce a diuretic and simultaneously a saluretic effect upon administration of said dosage unit form of a compound of the formula I 1 CH2Q Z1 R-+-CO I Y Q COOH wherein Q is chloro or bromo;

2 33 UNITED STATES PATENT OFFICE QETIWCATE @F CQECTWN PatentNo: 3,67 ,5 Deted July 11, 1 72 Inv or JANOS MZERGENYI ET AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line [73] should read --=CIBAGEIGY' Corporation -3 Column 7, line 39, saturetically" should read saluretically Signed and sealed this 15th day of January 1971+.

(SEAL,

Attest:

EDWARD M. FLETCHER, JR. RENE D. TEGTME'YER Attesting Officer Acting Commissioner of Patents 

2. The method according to claim 1 wherein said compound is 5-(2-bromo-2-bromomethyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt of said compound with a base.
 3. A pharmaceutical composition comprising a combination in dosage unit form of a pharmaceutical carrier and an amount sufficient to produce a diuretic and simultaneously a saluretic effect upon administration of said dosage unit form of a compound of the formula I
 4. A composition according to claim 3 wherein said compound is 5-(2-bromo-2-bromomethyl-butyryl)-6-methyl-benzofuran-2-carboxylic acid or a pharmaceutically acceptable salt of said compound with a base. 